Despite therapeutic advances, multiple myeloma (MM) is generally incurable, and new and more effective treatment options are urgently needed. Inhibitor of apoptosis (IAP) antagonists/Smac-mimetics (SMs) such as LCL161 or birinopant, initially developed to prevent IAPs from inhibiting activated caspases and apoptosis, have shown pre-clinical potential as anti-cancer agents, including in MM. Recent attention has focused on the ability of SMs to down-regulate the core E3 ubiquitin ligases cIAP1/2, thereby inhibiting both the canonical and non-canonical NF-?B pathways, critical for MM cell survival, while activating the extrinsic apoptotic pathway through the ripoptosome. Histone deacetylase inhibitors (HDACIs) modulate gene expression and acetylation of numerous non-histone substrates. Notably, the HDACI panobinostat (PB) has very recently been approved (with proteasome inhibitors; PIs) in MM. Recently, we and others have demonstrated that HDACIs play important roles in regulation of the NF-?B and extrinsic apoptotic pathways. Here, we propose a novel mechanism-driven strategy combining SMs with HDACIs in MM based on multiple complementary rationales i.e., a) SMs and HDACIs target common signaling cascades, and in combination simultaneously inhibit both the canonical and non-canonical NF-?B pathways while activating the intrinsic and extrinsic apoptotic pathways; b) NF-?B is constitutively activated in MM cells due to frequent genetic aberrations and bone marrow microenvironmental factors; c) NF-?B inhibition (e.g., by PIs) significantly increases HDACI activity in MM. Indeed, preliminary evidence suggests highly synergistic interactions between SMs and HDACIs in various MM cell types. To advance this novel concept, three Aims are proposed. In Specific Aim #1, we will define MOAs by which SMs potentiate HDACI anti-MM activity, highlighting disruption of the canonical or non- canonical NF-?B pathways, and engagement of the extrinsic pathway via the ripoptosome; establish regimen efficacy in MM cells resistant to conventional or novel agents, particularly by bypassing acquired resistance due to aberrant Bcl-2 family expression through MOAs involving activation of the extrinsic apoptotic pathway; determine whether this strategy circumvents microenvironmental forms of drug-resistance by interrupting the non-canonical NF-?B pathway. In Specific Aim #2, we will determine whether the regimen selectively kills primary MM cells while sparing normal cells; test the hypothesis that this strategy also targets MM stem cell- like cells; determine whether certain primary MM cell subtypes with genetic aberrations involving NF-?B or apoptotic pathways are particularly sensitive to this regimen, and if so, which mechanisms are operative. In Specific Aim #3, we will test whether the regimen is effective and tolerated in immunocompromised or immunocompetent MM mouse models, and determine if MOAs identified in vitro are operative in vivo. If successful, these studies will provide the necessary foundation for clinical development of a new and potentially more effective individualized treatment strategy for relapsed/refractory MM.